Synthesis, binding and bioactivity of γ-methylene γ-lactam ecdysone receptor ligands: advantages of QSAR models for flexible receptors

Woldeamanuel Birru, Ross T. Fernley, Lloyd D. Graham, Julian Grusovin, Ronald J. Hill, Albert Hofmann, Linda Howell, Peter J. James, Karen E. Jarvis, Wynona M. Johnson, Dionne A. Jones, Christa Leitner, Andris J. Liepa, George O Lovrecz, Louis Lu, Roland H. Nearn, Brian J. O'Driscoll, Tram Phan, Matthew Pollard, Kathleen A. TurnerDavid A. Winkler

Research output: Contribution to journalArticleOther

25 Citations (Scopus)


Nuclear hormone receptors, such as the ecdysone receptor, often display a large amount of induced fit to ligands. The size and shape of the binding pocket in the EcR subunit changes markedly on ligand binding, making modelling methods such as docking extremely challenging. It is, however, possible to generate excellent 3D QSAR models for a given type of ligand, suggesting that the receptor adopts a relatively restricted number of binding site configurations or 'attractors'. We describe the synthesis, in vitro binding and selected in vivo toxicity data for γ-methylene γ-lactams, a new class of high-affinity ligands for ecdysone receptors from Bovicola ovis (Phthiraptera) and Lucilia cuprina (Diptera). The results of a 3D QSAR study of the binding of methylene lactams to recombinant ecdysone receptor protein suggest that this class of ligands is indeed recognised by a single conformation of the EcR binding pocket. 

Original languageEnglish
Pages (from-to)5647-5660
Number of pages14
JournalBioorganic & Medicinal Chemistry
Issue number15
Publication statusPublished - 1 Aug 2010
Externally publishedYes


  • Biological activity
  • Ecdysone receptor
  • Structure-activity relationships
  • Synthesis

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